This grant proposes phase I and II trials of several constructs of recombinant humanized anti-CD33 (HuG1-M195) for therapy of myelogenous leukemia. HuG1-M195 is a high affinity, recombinant human monoclonal antibody reactive with CD33, an antigen expressed by myelogenous leukemia cells. Previous clinical trials with murine M195 have shown that M195 rapidly targets, saturates and internalizes into myelogenous leukemia cells in different compartments of the body and, when radiolabeled, can kill more than 99% of leukemia cells even in refractory patients with high leukemia burden (> 1 kg). Murine 131/I-M195 is limited by lack of intrinsic effector activity, bystander cell kill due to the long range beta of iodine-131, and also neutralization by human anti-mouse antibody (HAMA). Therefore, several humanized M195 constructs were developed to solve these problems. In vitro, HuG1-M195 is capable of mediating specific antibody-dependent cellular cytotoxicity against acute myelogenous leukemia cells, particularly in the presence of low doses of IL-2. A Phase I trial of the HuG1-M195 suggests pharmacology, biodistribution and a safety profile similar to the mouse M195. In addition, no HAMA has been seen with the humanized form. Because of the rapid, specific and saturable delivery of M195 to leukemia cells at low doses, this antigen-antibody-disease system provides "proof of concept" tests of two basic applications of mAb and mAb constructs: Ablative therapy of large burden tumors and elimination of minimal disease after induction or debulking therapy. Each trial will focus on a different important issue: 3 constructs designed to kill large numbers of cells will be tested. Beta emitting 131/I-HuG1-M195 will be tested in a phase I/II trial before bone marrow transplant. Alpha-emitting 213/Bi-HuG1-M195 or a homo-dimeric HuG1-M195 (HdIgG-M195), (with enhanced biochemical properties) labeled with 131/I, will be tested in phase I trials. One strategy designed to kill smaller numbers of residual cells in patients in clinical remission or in early relapse will be tested also: HuG1-M195, that works via IL-2 upregulated ADCC (HuG1-M195 plus low dose IL-2), will be evaluated in a phase I trial. In these studies, PCR, FISH, and flow cytometric measures of minimal disease will be applied to assess outcome as well. Though leukemias are not among the most common neoplasms, the advantages of this system should lead to advances that may be applied generally.